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ESC GUIDELINES
2012 focused update of the ESC Guidelines
for the management of atrial fibrillationAn update of the 2010 ESC Guidelines for the management
of atrial fibrillation
Developed with the special contribution of the European HeartRhythm Association
Authors/Task Force Members: A. John Camm (Chairperson) (UK)*,
Gregory Y.H. Lip (UK), Raffaele De Caterina (Italy), Irene Savelieva (UK),
Dan Atar (Norway), Stefan H. Hohnloser (Germany), Gerhard Hindricks (Germany),Paulus Kirchhof (UK)
ESC Committee for Practice Guidelines (CPG): Jeroen J. Bax (CPG Chairperson) (The Netherlands),
Helmut Baumgartner (Germany), Claudio Ceconi (Italy), Veronica Dean (France), Christi Deaton (UK),
Robert Fagard (Belgium), Christian Funck-Brentano (France), David Hasdai (Israel), Arno Hoes (The Netherlands),
Paulus Kirchhof (Germany/UK), Juhani Knuuti (Finland), Philippe Kolh (Belgium), Theresa McDonagh (UK),
Cyril Moulin (France), Bogdan A. Popescu (Romania), Zeljko Reiner (Croatia), Udo Sechtem (Germany),
Per Anton Sirnes (Norway), Michal Tendera (Poland), Adam Torbicki (Poland), Alec Vahanian (France),
Stephan Windecker (Switzerland)
Document Reviewers: Panos Vardas (Review Coordinator) (Greece), Nawwar Al-Attar (France),
Ottavio Alfieri (Italy), Annalisa Angelini (Italy), Carina Blomstrom-Lundqvist (Sweden), Paolo Colonna (Italy),
Johan De Sutter (Belgium), Sabine Ernst (UK), Andreas Goette (Germany), Bulent Gorenek (Turkey),
Robert Hatala (Slovak Republic), Hein Heidbuchel (Belgium), Magnus Heldal (Norway), Steen Dalby Kristensen
(Denmark), Philippe Kolh (Belgium), Jean-Yves Le Heuzey (France), Hercules Mavrakis (Greece), Llus Mont
(Spain), Pasquale Perrone Filardi (Italy), Piotr Ponikowski (Poland), Bernard Prendergast (UK), Frans H. Rutten
(The Netherlands), Ulrich Schotten (The Netherlands), Isabelle C. Van Gelder (The Netherlands),
Freek W.A. Verheugt (The Netherlands)
The disclosure forms of the authors and reviewers are available on the ESC website www.escardio.org/guidelines
Representing the European Association for Cardio-Thoracic Surgery (EACTS).
Other ESC entities having participated in the development of this document:.
Associations: European Association of Echocardiography (EAE), European Association for Cardiovascular Prevention and Rehabilitation (EAPCR), Heart Failure Association (HFA).
Councils: Council for Cardiology Practice, Council on Primary Cardiovascular Care.
Working Groups: Acute Cardiac Care, Cardiovascular Surgery, Development, Anatomy and Pathology, Nuclear Cardiology and Cardiac Computed Tomography, Pharmacology and
Drug Therapy, Thrombosis, Valvular Heart Disease.
The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the
ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford
University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC.
* Corresponding authors: A. John Camm, Division of Clinical Sciences, St.Georges University of London, Cranmer Terrace, London SW17 0RE, United Kingdom.Tel.: +44 20 8725 3414. Fax: +44 20 8725 3416, Email: [email protected]
Disclaimer. The ESC Guidelines represent the views of the ESC and were arrived at after careful consideration of the available evidence at the time they were written. Health
professionals are encouraged to take them fully into account when exercising their clinical judgement. The Guidelines do not, however, override the individual responsibility of
health professionals to make appropriate decisions in the circumstances of the individual patients, in consultation with that patient and, where appropriate and necessary, the
patients guardian or carer. It is also the health professionals responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.
& The European Society of Cardiology 2012. All rights reserved. For permissions please email: [email protected]
European Heart Journal (2012) 33 , 27192747
doi:10.1093/eurheartj/ehs253
http://www.escardio.org/guidelinesmailto:[email protected]:[email protected]:[email protected]:[email protected]://www.escardio.org/guidelineshttp://www.escardio.org/guidelineshttp://www.escardio.org/guidelines -
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Keywords Atrial fibrillation European Society of Cardiology Guidelines Anticoagulation Novel oral
anticoagulants Left atrial appendage occlusion Rate control Cardioversion Rhythm control
Antiarrhythmic drugs Upstream therapy Pulmonary vein isolation Left atrial ablation Focused
update
Online publish-ahead-of-print 24 August 2012
Table of ContentsAbbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . . 2720
1.. Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2721
2.. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2722
3.. Stroke and bleeding risk assessment . . . . . . . . . . . . . . . . .2723
4.. Novel oral anticoagulants . . . . . . . . . . . . . . . . . . . . . . . . 2725
4.1. Dabigatran etexilate . . . . . . . . . . . . . . . . . . . . . . . . 2725
4.2. Rivaroxaban . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2725
4.3. Apixaban . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2726
4.4. Practical considerations . . . . . . . . . . . . . . . . . . . . . . 2726
5.. Left atrial appendage closure . . . . . . . . . . . . . . . . . . . . .2731
5.1. Rationale and techniques for left atrial appendage
closure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2731
5.2. Results of left atrial appendage closure . . . . . . . . . . .2732
6.. Cardioversion with pharmacological agents . . . . . . . . . . . .2732
6.1. Clinical evidence for vernakalant. . . . . . . . . . . . . . . . 2733
6.2. Safety of vernakalant . . . . . . . . . . . . . . . . . . . . . . .2733
7.. Oral antiarrhythmic drug therapy . . . . . . . . . . . . . . . . . . .2735
7.1. Upstream therapy . . . . . . . . . . . . . . . . . . . . . . . . .2735
7.2. Principles of antiarrhythmic drug therapy . . . . . . . . . .2735
7.3. Update on dronedarone . . . . . . . . . . . . . . . . . . . . . 2737
8.. Catheter ablation of atrial fibrillation . . . . . . . . . . . . . . . .2739
8.1. New evidence for catheter ablation . . . . . . . . . . . . .2739
8.2. Catheter ablation in patients with heart failure . . . . . .2740
8.3. Anticoagulant therapy peri-ablation . . . . . . . . . . . . . .2740
8.4. Safety first . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2741
8.5. New considerations for AF catheter ablation . . . . . . .2741
9.. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . .2741
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2742
Abbreviations and acronyms
ACCF American College of Cardiology Foundation
ACCP American College of Chest PhysiciansACS acute coronary syndrome
ACT Atrial arrhythmia Conversion Trial
ADONIS AmericanAustralianAfrican trial with
DronedarONe In atrial fibrillation or flutter for
the maintenance of Sinus rhythm
AF atrial fibrillation
AHA American Heart Association
ANDROMEDA ANtiarrhythmic trial with DROnedarone in
Moderate-to-severe congestive heart failure
Evaluating morbidity DecreAse
APHRS Asia Pacific Heart Rhythm Society
aPTT activated partial thromboplastin time
ARB angiotensin-receptor blocker
ARISTOTLE Apixaban for Reduction In STroke and Other
ThromboemboLic Events in atrial fibrillation
ATHENA A placebo-controlled, double-blind, parallel
arm Trial to assess the efficacy of dronedarone
400 mg b.i.d. for the prevention of cardiovascular
Hospitalization or death from any cause in
patiENts with Atrial fibrillation/atrial flutter
ATRIA AnTicoagulationand Riskfactors InAtrialfibrillation
AVERROES Apixaban VErsus acetylsalicylic acid (ASA) toReduce the Rate Of Embolic Stroke in atrial
fibrillation patients who have failed or are unsuit-
able for vitamin K antagonist treatment
AVRO A prospective, randomized, double-blind, Active-
controlled, superiority study of Vernakalant vs.
amiodarone in Recent Onset atrial fibrillation
b.i.d bis in die (twice daily)
b.p.m. beats per minute
CABANA Catheter ABlation vs. ANtiarrhythmic drug
therapy for Atrial fibrillation
CABG coronary artery bypass graft
CAP Continued Access to Protect AFCHA2DS2-VASc Congestive heart failure or left ventricular dys-
function Hypertension, Age 75 (doubled),
Diabetes, Stroke (doubled)-Vascular disease,
Age 6574, Sex category (female)
CHADS2 Congestive heart failure, Hypertension, Age
75, Diabetes, Stroke (doubled)
CI confidence interval
CRAFT Controlled Randomized Atrial Fibrillation Trial
CrCl creatinine clearance
DAFNE Dronedarone Atrial Fibril latioN study after
Electrical cardioversion
DIONYSOS Randomized Double blind trIal to evaluate
efficacy and safety of drOnedarone (400 mg
b.i.d.) vs. amiodaroNe (600 mg q.d. for 28 daYS,
then 200 mg qd thereafter) for at least 6
mOnths for the maintenance of Sinus rhythm in
patients with atrial fibrillation
EAST Early treatment of Atrial fibrillation for Stroke
prevention Trial
EHRA European Heart Rhythm Association
ECG electrocardiogram
EMA European Medicines Agency
ERATO Efficacy and safety of dRonedArone for The
cOntrol of ventricular rate during atrial fibrillation
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EURIDIS EURopean trial In atrial fibrillation or flutter
patients receiving Dronedarone for the maInten-
ance of Sinus rhythm
FAST atrial Fibril lation catheter Ablation vs. Surgical
ablation Treatment
FDA Food and Drug Administration
Flec-SL Flecainide Short-Long trial
HAS-BLED Hypertension, Abnormal renal/liver function,Stroke, Bleeding history or predisposition,
Labile INR, Elderly, Drugs/alcohol concomitantly
HF-PEF heart failure with preserved ejection fraction
HF-REF heart failure with reduced ejection fraction
HR hazard ratio
HRS Heart Rhythm Society
ICH intracranial haemorrhage
INR international normalized ratio
i.v. intravenous
J-RHYTHM Japanese RHYTHM management trial for atrial
fibrillation
LAA left atrial appendage
LoE level of evidence
LVEF left ventricular ejection fraction
MANTRA-PAF Medical ANtiarrhythmic Treatment or
Radiofrequency Ablation in Paroxysmal Atrial
Fibrillation
NICE National Institute for Health and Clinical
Excellence
NOAC novel oral anticoagulant
NSAID non-steroidal anti-inflammatory drug
NYHA New York Heart Association
OAC oral anticoagulant or oral anticoagulation
o.d. omni die(every day)
PALLAS Permanent Atrial fibriLLAtion outcome Studyusing dronedarone on top of standard therapy
PCI percutaneous coronary intervention
PREVAIL Prospective Randomized EVAluation of the LAA
closure device In patients with atrial fibrillation
vs. Long-term warfarin therapy
PROTECT AF WATCHMAN LAA system for embolic
PROTECTion in patients with Atrial Fibrillation
PT prothrombin time
RAAFT Radio frequency Ablation Atrial Fibrillation Trial
RE-LY Randomized Evaluation of Long-term
anticoagulant therapY with dabigatran etexilate
ROCKET-AF Rivaroxaban Once daily oral direct factor Xainhibition Compared with vitamin K antagonism
for prevention of stroke and Embolism Trial in
atrial fibrillation
RRR relative risk reduction
TE thromboembolism
TIA transient ischaemic attack
t.i.d. ter in die (three times daily)
TOE transoesophageal echocardiogram
TTR time in therapeutic range
VKA vitamin K antagonist
1. Preamble
Guidelines summarize and evaluate all currentlyavailable evidence on
a particular issue with the aim of assisting physicians in selecting the
best management strategy for an individual patient suffering from a
given condition, taking into account the impact on outcome, as well
as the risk benefit ratio of particular diagnostic or therapeutic
means. Guidelines are no substitutes for textbooks. The legal implica-tions of medical guidelines have been discussed previously.
A large number of guidelines have been issued in recent years by
the European Society of Cardiology (ESC) as well as by other so-
cieties and organizations. Because of the impact on clinical practice,
quality criteria for development of guidelines have been established
in order to make all decisions transparent to the user. The recom-
mendations for formulating and issuing ESC Guidelines can be
found on the ESC web site (http://www.escardio.org/guidelines-
surveys/esc-guidelines/about/Pages/rules-writing.aspx).
In brief, experts in the field are selected and undertake a com-
prehensive review of the published evidence for management and/
or prevention of a given condition. A critical evaluation of diagnos-
tic and therapeutic procedures is performed, including assessment
of the riskbenefit ratio. Estimates of expected health outcomes
for larger societies are included, where data exist. The level of evi-
dence and the strength of recommendation of particular treatment
options are weighed and graded according to pre-defined scales, as
outlined in Tables1 and 2 .
The experts of the writing panels have provided disclosure
statements of all relationships they may have that might be per-
ceived as real or potential sources of conflicts of interest. These
disclosure forms are kept on file at the European Heart House,
headquarters of the ESC. Any changes in conflict of interest that
arise during the writing period must be notified to the ESC. The
Task Force report received its entire financial support from theESC and was developed without any involvement of the pharma-
ceutical, device, or surgical industries.
The ESC Committee for Practice Guidelines (CPG) supervises
and coordinates the preparation of new guidelines produced by
Task Forces, expert groups, or consensus panels. The Committee
is also responsible for the endorsement process of these guidelines
or statements. Once the document has been finalized and
approved by all the experts involved in the Task Force, it is submit-
ted to outside specialists for review. The document is revised,
finally approved by the CPG, and subsequently published.
After publication, dissemination of the message is of paramount
importance. Pocket-sized versions and personal digital assistant
(PDA) downloadable versions are useful at the point of care.
Some surveys have shown that the intended users are sometimes
unaware of the existence of guidelines, or simply do not translate
them into practice. Thus, implementation programmes for new
guidelines form an important component of knowledge dissemin-
ation. Meetings are organized by the ESC and directed towards
its member National Societies and key opinion leaders in
Europe. Implementation meetings can also be undertaken at na-
tional levels, once the guidelines have been endorsed by the ESC
member societies and translated into the national language. Imple-
mentation programmes are needed because it has been shown that
ESC Guidelines 2721
http://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspxhttp://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspxhttp://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspxhttp://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspxhttp://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspxhttp://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspxhttp://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspxhttp://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspxhttp://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspx -
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the outcome of disease may be favourably influenced by the thor-
ough application of clinical recommendations.
Thus, the task of writing guidelines covers not only the
integration of the most recent research, but also the creation of
educational tools and implementation programmes for the recom-
mendations. The loop between clinical research, writing of guide-
lines, and implementing them into clinical practice can then only
be completed if surveys and registries are performed to verify
that real-life daily practice is in keeping with what is recommended
in the guidelines. Such surveys and registries also make it possible
to evaluate the impact of implementation of the guidelines on
patient outcomes. Guidelines and recommendations should help
the physicians to make decisions in their daily practice; however,
the ultimate judgment regarding the care of an individual patient
must be made by the physician in charge of their care.
2. Introduction
The current estimate of the prevalence of atrial fibrillation (AF) in
the developed world is approximately 1.5 2% of the general
population, with the average age of patients with this condition
steadily rising, such that it now averages between 75 and 85
years. The arrhythmia is associated with a five-fold risk of stroke
and a three-fold incidence of congestive heart failure, and higher
mortality. Hospitalization of patients with AF is also very
common. This arrhythmia is a major cardiovascular challenge in
modern society and its medical, social and economic aspects are
all set to worsen over the coming decades. Fortunately a
number of valuable treatments have been devised in recent years
that may offer some solution to this problem.
In 2010, when the ESC Guidelines for the Management of AtrialFibrillation were first issued,1 it was already realized that an update
would be necessary in 2012 because, for example, European regu-
latory approvals of several new drugs were anticipated, such
as vernakalant and dabigatran. In addition, reports from major
clinical trials of the novel oral anticoagulants, such as AVERROES
(Apixaban VErsus acetylsalicylic acid (ASA) to Reduce the Rate
Of Embolic Stroke in atrial fibrillation patients who have failed
or are unsuitable for vitamin K antagonist treatment),2
ROCKET-AF (Rivaroxaban Once daily oral direct factor Xa inhib-
ition Compared with vitamin K antagonism for prevention of
stroke and Embolism Trial in Atrial Fibrillation),3 and ARISTOTLE
(Apixaban for Reduction In STroke and Other ThromboemboLicEvents in atrial fibrillation),4 were expected, paving the way for po-
tentially yet more regulatory approvals. What was not necessarily
expected was the early discontinuation of the PALLAS (Permanent
Atrial fibriLLAtion outcome Study) of dronedarone,5 nor the
reports of hepatotoxicity associated with this drug.
The American College of Cardiology Foundation (ACCF),
American Heart Association (AHA), and the Heart Rhythm
Society (HRS) have jointly published two major updates, one con-
cerning dronedarone and left atrial ablation,6 and another focusing
on dabigatran.7 Early in 2012, the American College of Chest
Physicians (ACCP) published its 9th version of Antithrombotic
Therapy for Atrial Fibrillation,8 and the Canadian Cardiovascular
Table 1 Classes of recommendations
Classes of
recommendationsDefinition Suggested wording to use
Class I Evidence and/or general agreement
that a given treatment or procedure
is beneficial, useful, effective.
Is recommended/is
indicated
Class II Conflicting evidence and/or a
divergence of opinion about the
usefulness/efficacy of the given
treatment or procedure.
Class IIa Weight of evidence/opinion is in
favour of usefulness/efficacy.
Should be considered
Class IIb Usefulness/efficacy is less well
established by evidence/opinion.
May be considered
Class III Evidence or general agreement that
the given treatment or procedure
is not useful/effective, and in some
cases may be harmful.
Is not recommended
Table 2 Levels of evidence
Level of
evidence A
Data derived from multiple randomized
clinical trials or meta-analyses.
Level of
evidence B
Data derived from a single randomized
clinical trial or large non-randomized
studies.
Level of
evidence C
Consensus of opinion of the experts and/
or small studies, retrospective studies,
registries.
ESC Guidelines2722
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Society guideline writers have issued a focused update of their AF
Guidelines.9 Also, the United Kingdoms National Institute for
Health and Clinical Excellence (NICE) and the ACCF, AHA, and
HRS intend to completely rewrite their AF Guidelines in the
near future.
Clinical outcomes research in AF continues at a fast pace. Also,
considerably more clinical experience has been gathered in the
fields of anticoagulation, atrial appendage occlusion, antiarrhythmicdrug use for cardioversion and rhythm control, and left atrial abla-
tion.10 These five areas form the bulk of the revisions to our
recommendations.
Screening for atrial fibrillation
Diagnosing AF before the first complications occur is a recognized
priority for the prevention of strokes.11 Recent data collected in
patients with implanted devices,12 and by Holter electrocardio-
grams (ECGs) in epidemiological studies,13 reinforce the assump-
tion that even short episodes of silent AF convey an increased
risk for stroke. We therefore recommend that, in patients aged
65 years or over, opportunistic screening for AF by pulse palpa-
tion, followed by recording of an ECG to verify diagnosis, shouldbe considered for the early detection of AF.14,15
Key point
In patients 65 years or older, opportunistic screening by pulse
palpation, followed by an ECG in those with an irregular pulse,
is important to detect AF prior to the first stroke.
3. Stroke and bleeding risk
assessmentIt is conventional to divide AF into cases which are described as
valvular or non-valvular. No satisfactory or uniform definition
of these terms exists. In this guideline, the term valvular AF is
used to imply that AF is related to rheumatic valvular disease (pre-
dominantly mitral stenosis) or prosthetic heart valves.
Since the publication of the 2010 ESC Guidelines, additional evi-
dence has strengthened the use of the risk factor-based approach
to stroke risk stratification proposed in that guideline, with more
focus on the identification of truly low-risk patients who do not
need any antithrombotic therapy, and more evidence on the use
of novel oral anticoagulant drugs (NOACs; see below) as
alternatives to dose-adjusted vitamin K antagonist (VKA) therapy
[e.g. warfarin, international normalized ratio (INR) 2.03.0].16
Stroke risk is a continuum and the predictive value of artificially
categorizing AF patients into low, moderate, and high-risk strata
only has modest predictive value for identifying the high-risk cat-
egory of patients who would subsequently suffer strokes.17 Until re-
cently, the only oral anticoagulant (OAC) available was the VKA
class of drugs (e.g. warfarin) and, despite its limitations, many physi-cians still prescribed VKA therapy in broadly similar proportions, ir-
respective of the categorization into low/moderate/high-risk strata; if
a VKA was not used, aspirin was often prescribed instead.18,19
The evidence for effective stroke prevention with aspirin in AF is
weak, with a potential for harm,2022 as data indicate that the risk
of major bleeding or intracranial haemorrhage (ICH) with aspirin is
not significantly different to that of OAC, especially in the
elderly.2,2325 Given the availability of NOACs, the use of antipla-
telet therapy (such as aspirin clopidogrel combination therapy,
orless effectivelyaspirin monotherapy) for stroke prevention
in AF should be limited to the few patients who refuse any form
of OAC. Aspirinclopidogrel combination therapy has additional
efficacy, compared with aspirin monotherapy, but at additional
risk for major bleeding.26 Thus, aspirin monotherapy should be
confined to those who refuse any OAC and cannot tolerate
aspirinclopidogrel combination therapy due, for example, to ex-
cessive bleeding risk. There is no evidence for the decrease in total
or cardiovascular mortality with aspirin (or antiplatelet drugs) in the
AF population. Even in non-AF populations, aspirin prophylaxis in
people without prior cardiovascular disease does not lead to reduc-
tions in either cardiovascular or cancer mortality and the benefits in
non-fatal myocardial infarctiion are further offset by clinically import-
ant bleeding events.27
Thus, this guideline strongly recommends a practice shift towards
greater focus on identification of truly low-risk patients with AF (i.e.age ,65 and lone AF, who do not need any antithrombotic
therapy), instead of trying to focus on identifying high-risk patients.
To achieve this, it is necessary to be more inclusive (rather than
exclusive) of common stroke risk factors as part of any compre-
hensive stroke risk assessment. Indeed, patients with AF who
have stroke risk factor(s) 1 are recommended to receive effect-
ive stroke prevention therapy, which is essentially OAC with either
well-controlled VKA therapy [INR 23, with a high percentage of
time in the therapeutic range (TTR), for example, at least 70%]28
or one of the NOACs.
Whilst the CHADS2 [Congestive heart failure, Hypertension,
Age 75, Diabetes, Stroke (doubled)] score is simple,
29
mostnow agree that it does not include many common stroke risk
factors and its limitations have been highlighted.30,31 The
CHADS2 score was also derived from risk factors identified in
datasets of the non-VKAtreated patients in the historical trials
of stroke prevention in AF conducted two decades ago. In these
trials, fewer than 10% of the patients screened were included,
and many stroke risk factors were inconsistently defined or were
not systematically recorded.17 For example, vascular disease (not
included in the CHADS2 score) is an independent risk factor for
stroke in AF and significantly improves the predictive ability of
CHADS2.3234 The risk of stroke also increases from age 65
years, with even greater risk at age 75 years or older.32,35,36
Recommendation for screening of AF
Recommendations Classa Level b RefC
Opportunistic screening forAF in patients 65 years of ageusing pulse-taking followed by
an ECG is recommended toallow timely detectionof AF.
I B 14, 15
AF atrial fibrillation; ECG electrocardiogram.aClass of recommendation.bLevel of evidence.cReferences.
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Many patients classified as low-risk using CHADS2 (score 0)
have stroke rates .1.5%/year,29,36 and a CHADS2 score of 0
does not reliably identify AF patients who are truly low-risk.37,38
The 2010 ESC Guidelines on AF1 de-emphasized the use of the
artificial low-, moderate-, and high-risk strata and recommended a
risk factor-based approach defining major and clinically relevant
non-major risk factors, which can be expressed as an acronym,
CHA2DS2-VASc (Congestive heart failure/left ventricular dysfunc-
tion, Hypertension, Age 75 [doubled], Diabetes, Stroke
[doubled] Vascular disease, Age 6574, and Sex category
[female]).39
Given that guidelines should be applicable to most AF patientsfor most of the time and for most situations in everyday clinical
practice, the ESC Guideline stroke risk assessment approach
covers most of the AF patients seen and considers the common
stroke risk factors in such patients. Antithrombotic therapy is
not recommended in patients with AF (irrespective of gender)
who are aged ,65 and lone AF (i.e. truly low-risk), as the
latter have very low absolute event rates.
The CHA2DS2-VASc score is inclusive of the most common
stroke risk factors in everyday clinical practice.3941 Contrary to
older, conflicting (and weak) data, thyroid disease (or hyperthy-
roidism) is not considered to be an independent stroke risk
factor on multivariable analysis (Table 3).25 A history of any
heart failure per se is not consistently defined as a risk
factor,25,40 and the C in CHA2DS2-VASc refers to documented
moderate-to-severe systolic dysfunction [i.e. heart failure with
reduced ejection fraction (HF-REF)]42,43 or patients with recent
decompensated heart failure requiring hospitalization, irrespective
of ejection fraction [i.e. both HF-REF and heart failure with pre-
served ejection fraction (HF-PEF)].43 Female gender independently
increases the risk of stroke overall (Table3),40,44,45
unless the cri-terion of age ,65 and lone AF is clearly fulfilled, whereby female
gender does not independently increase stroke risk.33,44 Moreover,
stroke rates in these patients (age ,65 and lone AF) are so low in
both males and females that antithrombotic therapy is not recom-
mended. Thus, female patients with gender alone as a single risk
factor (still a CHA2DS2-VASc score of 1) would not need anticoa-
gulation if they clearly fulfil the criteria of age , 65 and lone AF,
as confirmed in recent studies.33,44
The CHA2DS2-VASc score has since been validated in multiple
cohorts;17 the accumulated evidence shows that CHA2DS2-VASc
is better at identifying truly low-risk patients with AF37,38,46,47
and is as good as, and possibly better than, scores such as
CHADS2in identifying patients who develop stroke and thrombo-
embolism.25,36,48 Amongst patients with CHADS2 score 0, the
1-year event rates can range between 0.84% (CHA2DS2-VASc
score 0), 1.75% (CHA2DS2-VASc score 1), 2.69% (CHA2DS2-
VASc score 2), and 3.2% (CHA2DS2-VASc score 3).38 Also,
CHA2DS2-VASc refines stroke risk assessment in low-risk AF
patients after ablation.49
AF patients with severe renal failure are at high risk for stroke,
but are also at increased risk for death, coronary events and
serious bleeding. These patients have not been adequately
studied and have been excluded from clinical trials, and their risk
assessment is complex.50 There is also the caveat that renal func-
tion may not remain static, especially in elderly AF patients withmultiple comorbidities and concomitant drug therapies.
Decision-making for thromboprophylaxis needs to balance the
risk of stroke against the risk of major bleeding, especially ICH,
which is the most feared complication of anticoagulation therapy
and confers a high risk of death and disability.51 Until recently,
bleeding risk assessment tools were based on complex formulae,
with certain risk factors weighted in different ways and/or
derived from cohorts of anticoagulated patients, rather than specif-
ically from AF patients.52 Of the available bleeding risk scores,
only three have been derived and validated in AF populations:
HEMORR2HAGES [Hepatic or renal disease, Ethanol abuse, Malig-
nancy, Older (age 75 years), Reduced platelet count or function,Rebleeding risk, Hypertension (uncontrolled), Anaemia, Genetic
factors, Excessive fall risk, and Stroke],53 HAS-BLED [Hyperten-
sion, Abnormal renal/liver function, Stroke, Bleeding history or
predisposition, Labile INR, Elderly (e.g. age .65, frailty, etc.),
Drugs/alcohol concomitantly],54 and ATRIA (AnTicoagulation
and Risk factors In Atrial fibrillation).55
The 2010 ESC Guidelines on AF,1 Canadian Cardiovascular
Society Guidelines (recently updated).9,56 and the consensus docu-
ment on bleeding in AF, prepared by the European Heart Rhythm
Association (EHRA) and the ESC Working Group on Throm-
bosis,52 all recommended use of the simple bleeding risk assess-
ment score, HAS-BLED, rather than the more complicated
Table 3 Risk factors for ischaemic stroke/TIA/
systemic embolism in patients with AF: the Swedish
Cohort Atrial Fibrillation study (adapted from Friberg
et al.25)
Multivariate hazard ratios
(95% CI)
Age (years)
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HEMORR2HAGES score, or the less practical ATRIA score. The
HAS-BLED score has better predictive value than that of ATRIA
and, importantly, highlights risk factors that can be actively
managed to reduce the bleeding risk.57,58 The HAS-BLED score
has been validated in several independent cohorts,25,54,5961 and
correlates well with ICH risk. It is noteworthy that the ICH
(and major bleeding) rate in patients on aspirin, for a given
HAS-BLED score, was similar to that for those taking warfarin.25
Thus, a formal bleeding risk assessment is recommended for all
patients with AF, and in patients with a HAS-BLED score 3,
caution and regular review are appropriate, as well as efforts to
correct the potentially reversible risk factors for bleeding. The
HAS-BLED score per se should not be used to exclude patients
from OAC therapy but allows clinicians to make an informed as-
sessment of bleeding risk (rather than relying on guesswork) and,
importantly, makes them think of the correctable risk factors for
bleeding: for example, uncontrolled blood pressure, concomitant
use of aspirin/non-steroidal anti-inflammatory drugs (NSAIDs),
labile INRs, etc. Use of the CHA2DS2-VASc and HAS-BLED
scores to aid practical decision-making for thromboprophylaxis
in non-valvular AF has recently been reviewed.62
In the net clinical benefit analysisbalancing ischaemic stroke
against intracranial bleedingby Olesen et al.,21 those patients
with a high HAS-BLED score had an even greater net clinical
benefit with warfarin, given that the higher-risk individuals would
have a much greater absolute reduction in stroke risk with war-
farin, which would outweigh the small absolute increase in major
bleeding events. Similar observations were reported in a much
larger dataset by Friberg et al.,63 where the adjusted net clinical
benefit favoured anticoagulation for almost all AF patients, with
the exception of patients at very low risk of ischaemic stroke,
with a CHA2DS2-VASc score of 0 and moderatehigh bleeding
risk. In the two large independent datasets,21,63 the CHA2DS2-VASc score was able to identify those patients who had some dis-
advantage from anticoagulant treatment with warfarin. Notably,
the CHADS2 score was less discriminatory for truly low-risk
patients, where all AF patients, irrespective of CHADS2 score,
appeared to benefit from anticoagulation use.63
Additional evidence emphasizes that stroke prevention with a
VKA is effective where the individual mean time in therapeutic
range (TTR) is good; for example .70%.28,6467 Thus, where a
VKA is used, efforts to improve quality of INR control are
needed in order to achieve high TTRs.
4. Novel oral anticoagulants
The NOACs for stroke prevention in AF fall into two classes:
the oral direct thrombin inhibitors (e.g. dabigatran) and oral
direct factor Xa inhibitors (e.g. rivaroxaban, apixaban, etc.).68 In
contrast to VKAs, which block the formation of multiple active
vitamin K-dependent coagulation factors ( factors II, VII, IX, and
X), these drugs block the activity of one single step in coagula-
tion. Another oral factor Xa inhibitor with an ongoing,
large phase III trial is edoxaban; this will probably be reported
in 2013.69
4.1 Dabigatran etexilateThe RE-LY (Randomized Evaluation of Long-term anticoagulant
therapY with dabigatran etexilate) trial was a prospective, rando-
mized, open-label, phase III trial comparing two blinded doses of
dabigatran etexilate [110 mg b.i.d. (D110) or 150 mg b.i.d.
(D150)] with open-label adjusted-dose warfarin, aiming for an
INR of 2.03.0 (Table 4).70,71 For the primary efficacy endpoint
of stroke and systemic embolism, D150 was superior to warfarin,
with no significant difference in the primary safety endpoint of
major bleeding. D110 was non-inferior to warfarin, with 20%
fewer major bleeds. Rates of haemorrhagic stroke and ICH were
lower with both doses of dabigatran, but gastrointestinal bleeding
was significantly increased with D150. There was a non-significant
numerical increase (of 28%) in myocardial infarction (MI) with both
dabigatran doses.71,72 There was a significant reduction in ischae-
mic stroke, as well as a borderline reduction in all-cause mortality
with D150 (P 0.051) and a significant reduction in vascular mor-
tality (P 0.04). The rates of discontinuation were higher with
D150 (20.7%) and D110 (21.2%), compared with 16.6% with war-
farin at 2 years. A post-hoc analysis has reported a significant ageinteraction, whereby patients aged .75 years had rates of major
bleeding similar to warfarin with D110, with a trend towards
more bleeding with D150; however, ICH was lower with both
doses of dabigatran. The efficacy and safety of dabigatran was con-
sistent across all CHADS2 risk strata.73 Previous VKA exposure
does not influence the benefits of dabigatran at either dose, com-
pared with warfarin.74
The concerns over the small increase in MI with dabigatran have
prompted a detailed analysis where there was no excess of new
angina hospitalizations or revascularization with dabigatran-treated
patients, with a vascular mortality and a net clinical benefit in
favour of dabigatran.72 A meta-analysis of seven dabigatran
studies (AF, venous thromboembolism, etc.) in over 30 000
patients showed a significant 33% increase in MI, but an 11% reduc-
tion in all-cause mortality, when dabigatran was compared to war-
farin.75 However, this may reflect a better protective effect of
warfarin against MI.76
Based on the results of RE-LY, dabigatran etexilate has been
approved by both the Food and Drug Administration (FDA) and
the European Medicines Agency (EMA), as well as in many coun-
tries worldwide, for prevention of stroke and systemic embolism.
The EMA indication is for patients with non-valvular AF with at
least one risk factor, namely: previous stroke, transient ischaemic
attack (TIA) or systemic embolism; LVEF ,40%; symptomatic
heart failure; and age 75 years or age 65 years with one ofthe following: diabetes, coronary artery disease or hypertension.
The FDA has approved the 150 mg b.i.d. dose, and the 75 mg
b.i.d. dose in severe renal impairment, while the EMA has approved
both the 110 mg b.i.d. and 150 mg b.i.d. doses.
4.2 RivaroxabanThe double-blind ROCKET-AF3 trial randomized 14 264 high-risk
patients with AF to either (i) treatment with rivaroxaban 20 mg
o.d. [15 mg daily for those with estimated creatinine clearance
(CrCl) 3049 mL/min] or (ii) warfarin (Table 4). The population
ESC Guidelines 2725
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was at considerably higher risk for stroke than in other NOAC AF
trials, and the mean TTR was 55% (median 58%), which was lower
than in other randomized trials. Rivaroxaban was non-inferior to
warfarin for the primary endpoint of stroke and systemic embol-
ism, and the per-protocol on-treatment analysis achieved statistical
superiority [relative risk reduction (RRR) 21%, P 0.015] but,
using the more conventional intention-to-treat analysis, rivaroxa-
ban was not superior (P
0.12). There was no reduction inrates of mortality or ischaemic stroke, but a significant reduction
in haemorrhagic stroke and intracranial haemorrhage. The
primary safety endpoint was the composite of major- and clinically
relevant non-major bleeding, which was not significantly different
between rivaroxaban and warfarin but, with rivaroxaban, there
was a significant reduction in fatal bleeding, as well as an increase
in gastrointestinal bleeds and bleeds requiring transfusion. Prema-
ture discontinuation of treatment was more common with rivarox-
aban (23.9%) than with warfarin (22.4%).
Rivaroxaban has been approved for stroke prevention in non-
valvular AF by both the FDA and the EMA, and in many countries
worldwide.
4.3 ApixabanThe AVERROES trial2 randomized 5599 AF patients, who were not
suitable candidates foror were unwilling to takeVKA treat-
ment, to double-blind, double-dummy treatment with either apix-
aban [5 mg b.i.d. with a dose adjustment to 2.5 mg b.i.d. in patients
80 years, weight 60kg or with a serum creatinine 1.5 mg/dL
(133 mmol/L)] or aspirin (81 324 mg/day, with 91% taking
162 mg/day). After a mean follow-up of 1.1 years, the trial was
stopped early, due to a significant 55% reduction in the primary
endpoint of stroke or systemic embolism with apixaban comparedwith aspirin, with no significant difference in rates of major bleeding
or ICH between apixaban and aspirin. Apixaban was slightly better
tolerated, with rates of permanent discontinuation of study treat-
ments being 20.5% per year in the aspirin group, vs. 17.9% per
year in the apixaban group at 2 years (P 0.03).
The ARISTOTLE trial4 was a randomized, double-blind, double-
dummy, phase III trial comparing apixaban [5 mg b.i.d. with a dose
adjustment to 2.5 mg b.i.d. in patients 80 years, weight 60kg or
with a serum creatinine 1.5 mg/dL (133 mmol/L)] with
dose-adjusted warfarin aiming for an INR of 2.03.0 in 18 201
patients with non-valvular AF (Table4). There was a significant re-
duction in the primary efficacy outcome of stroke or systemic em-bolism by 21% with apixaban compared with warfarin, with a 31%
reduction in major bleeding and a significant 11% reduction in all-
cause mortality (but not cardiovascular mortality). Rates of haem-
orrhagic stroke and ICHbut not of ischaemic strokewere sig-
nificantly lower in patients treated with apixaban than with
warfarin. Gastrointestinal bleeding was similar between the treat-
ment arms. Apixaban was better tolerated than warfarin, with
slightly fewer early discontinuations (25.3% vs. 27.5%). Apixaban
has not yet gained regulatory approval from the EMA or FDA. It
is included in these guidelines because it may be approved
shortly after the publication.
4.4 Practical considerationsa
The NOACs so far tested in clinical trials have all shown non-
inferiority compared with VKAs, with better safety, consistently
limiting the number of ICH. On this basis, this guideline now
recommends them as broadly preferable to VKA in the vast major-
ity of patients with non-valvular AF, when used as studied in the
clinical trials performed so far. Since there is still limited
experience with these agents, strict adherence to approved
indications and careful post-marketing surveillance are strongly
recommended.
In the absence of head-to-head trials, it is inappropriate to be
definitive on which of the NOACs is best, given the heterogeneity
of the different trials.77 Indirect comparison analyses do not
suggest profound differences in efficacy endpoints between the
NOACs, but major bleeding appears lower with dabigatran
110mg b.i.d. and apixaban.77 Patient characteristics, drug tolerabil-
ity, and cost may be important considerations.28 Some cost-
effectiveness data for dabigatran have been published in various
healthcare settings, and dabigatran appears to be cost-effective
for most patients,7881
except in those with very well-controlledINRs. Also, there remain concerns over the applicability of data
for the NOACs to very elderly patients with multiple comorbid-
ities, polypharmacy, compliance issues etc., who are often
managed by primary care physicians. None of the novel OACs
has a specific antidote; dabigatran and apixaban have twice daily
dose regimens, and some drug interactions are evident. Patients
with severe renal impairment were excluded from the trials and,
specifically, dabigatran has a high renal clearance.
The net clinical benefit of VKAs, balancing ischaemic stroke
against ICH in patients with non-valvular AF, has been modelled
on to stroke and bleeding rates from the Danish nationwide
cohort study for dabigatran, rivaroxaban, and apixaban, on the
basis of recent clinical trial outcome data for these NOACs.82 At
a CHA2DS2-VASc score of 1, apixaban and both doses of dabiga-
tran (110 mg b.i.d. and 150 mg b.i.d.) had a positive net clinical
benefit while, in patients with CHA2DS2-VASc score 2, all
three NOACs were superior to warfarin, with a positive net
clinical benefit, irrespective of bleeding risk.
When switching from a VKA to a NOAC, the INR should be
allowed to fall to about 2.0 (there are NOAC-specific and transat-
lantic differences detailed in the Summaries of Product Character-
istics/Package Inserts, but the principle is to judge the waning effect
of warfarin against the increasing anticoagulant effect of the
NOAC) before starting the NOAC, all of which have rapid
onset of anticoagulation effect. When changing from a NOAC toa VKA, the VKA should be started after a period that depends
on renal function as, for example, with dabigatran, where overlap
with VKA for 23 days is necessary, as VKAs would take a few
days to achieve therapeutic anticoagulation.
Compliance and adherence to treatment is crucial, especially
since these drugs have a relatively short half-life, such that patients
would be left without any anticoagulation protection if more than
one dose were missed. All of these drugs have a degree of renal
a (Note: Given the multiple considerations on how to safely use NOAC in daily clinical
practice in different clinical scenarios, EHRA has prepared additional educational ma-
terial and a regularly updated website specifically addressing this.)
ESC Guidelines2726
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Table 4 Summary of the clinical trials involving novel anticoagulants vs. warfarin for stroke prevention in non-valvular
AF
Dabigatran (RE-LY)70, 71 Rivaroxaban (ROCKET-AF)3 Apixaban (ARISTOTLE)4
Drug characteristics
Mechanism Oral direct thrombin inhibitor Oral direct factor Xa inhibitor Oral direct factor Xa inhibitor
Bioavailability, % 6 6080 50
Time to peak levels, h 3 3 3
Half-life, h 1217 513 914
Excretion 80% renal 2/3 liver, 1/3 renal 25% renal, 75% faecal
Dose 150 mg b.i.d. 20 mg o.d. 5 mg b.i.d.
Dose in renal impairment 110 mg b.i.d. 15 mg o.d. (if CrCl 30-49 mL/min) 2.5 mg b.i.d.
Special considerations Intestinal absorption is pH-dependent and is
reduced in patients taking proton pump inhibitors
Higher levels expected in patients
with renal or hepatic failure
Increased risk of bleeding in patients taking
verapamil/amiodarone/quinidine/ketoconazole
Activity lower in fasted patients so
should be taken after food
Study characteristics
Study design Randomized, open-label Randomized, double-blind Randomized, double-blind
Number of patients 18 111 14 264 18 201
Follow-up period, years 2 1.9 1.8
Randomized groups Dose-adjusted warfarin vs. blinded doses of
dabigatran (150 mg b.i.d., 110 mg b.i.d.)
Dose-adjusted warfarin vs.
rivaroxaban 20 mg o.d.
Dose-adjusted warfarin vs. apixaban
5 mg b.i.d.
Baseline patient characteristics
Age, years 71.5 8.7 (mean SD) 73 (6578) [median (interquartile
range)]
70 (6376) [median (interquartile range)]
Male sex, % 63.6 61.3 64.5
CHADS2(mean) 2.1 3.5 2.1
Outcomes (% per year)
Warfarin Dabigatran 150 Dabigatran 110 Warfarin Rivaroxaban Warfarin Apixaban
(n= 6022) (n= 6076) (n= 6015) (n= 7133) (n= 7131) (n= 9081) (n= 9120)
(RR, 95% CI;
Pvalue)
(RR, 95% CI;
Pvalue)
(HR, 95% CI;
Pvalue)
(HR, 95% CI;
Pvalue)
Stroke/systemic embolism 1.69 1.11 (0.66,
0.530.82;
Pfor superiority
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excretion, especially dabigatran. Thus, assessment of renal function
(by CrCl) is mandatory for all NOACs, but especially for patients
taking dabigatran. Indeed, renal function should be assessed annu-
ally in patients with normal (CrCl 80 mL/min) or mild (CrCl 50
79 mL/min) renal impairment, and perhaps 23 times per year in
patients with moderate (i.e. creatinine clearance 3049 mL/min)
renal impairment. Dabigatran may also cause dyspepsia, which
may perhaps be ameliorated by taking the drug with food or the
use of a proton pump inhibitor.The NOACs do not require dose adjustment on the basis of a
specific coagulation test (in contrast to the INR for VKAs). There
are non-specific coagulation tests that can be used to check for the
presence of an anticoagulation effect (rather than anticoagulation
intensity per se).28,83 These should not be used for dose adjust-
ment). For dabigatran, the ecarin clotting time and thrombin clot-
ting time are useful tests, and directly reflect thrombin inhibition;84
however, an activated partial thromboplastin time (aPTT) can also
be used (especially in an emergency setting), although the correl-
ation is not linear, particularly at higher concentrations.84,85 Rivar-
oxaban prolongs the prothrombin time (PT) and this might be used
as a rough estimate of an anticoagulation effect.86
A better esti-mate for an anticoagulant effect for the oral Factor Xa inhibitors
is an anti-Xa assay.86,87
These novel drugs do not have specific antidotes and manage-
ment of bleeding is thus largely supportive, given that these
drugs have a relatively short (5 to 17 hours) half-life.85,88 One
small study suggested normalization of coagulation tests with non-
activated prothrombin complex concentrate (Cofactw, Sanquin
Blood Supply, Amsterdam, the Netherlands) administered to
healthy and relatively young individuals taking rivaroxaban, but
no effect was seen with dabigatran.89 Another study found that
low-dose FEIBAw (Baxter AG, Vienna, Austria) reversed the anti-
coagulant activity of rivaroxaban and dabigatran.90 However, the
lack of normalization of coagulation tests does not necessarily cor-
relate with the absence of an anti-haemorrhagic effect, as shown in
animal models.84
Perioperative management is another important consider-
ation.88,91 Given the rapid onset and offset of action of dabigatran
etexilate, no bridging therapy with low molecular weight heparin
(LMWH) is required for the majority of interventions, although
this is dependent upon balancing the risks of stroke/thrombo-
embolism vs. bleeding (where the HAS-BLED score has beenshown to be useful).92 Following surgery, NOACs can be restarted
as soon as effective haemostasis has been achieved. The NOAC
effect will be evident within a few hours after the first dose.
The available data suggest that elective cardioversion can be safely
performed on dabigatran,93 with the requirement for 3 weeks of
therapeutic anticoagulation pre-cardioversion, the cardioversion per-
formed, and anticoagulation continued for a minimum of 4 weeks
post-cardioversion. Event rates were not different between conven-
tional and trans-oesophageal echocardiogram-guided cardioversion;
however, drug compliance is crucial for the anticoagulation period
peri-cardioversion as, unlike the INR for VKAs, there is no easy
means to assess therapeutic anticoagulation. In patients with strokerisk factors or at high risk of recurrence, OAC should be continued
long-term, whether with a VKA or a NOAC. No published data on
cardioversion with rivaroxaban or apixaban are yet available.
There are currently no controlled data on the risk benefit
profile of catheter ablation on uninterrupted NOACs. Ablation
of a patient whilst still taking uninterrupted NOACs may carry a
small theoretical risk, given the lack of a reversal agent, should a
major bleeding complication arise. Data from limited case series
suggest that appropriate post-ablation management with dabiga-
tran is associated with a low risk of embolic or bleeding complica-
tions,94 although brief interruption of dabigatran use is associated
with more thromboembolic and bleeding complications.95
Table 4 Continued
Dabigatran (RE-LY)70, 71 Rivaroxaban (ROCKET-AF)3 Apixaban (ARISTOTLE)4
Outcomes (% per year)
Gastrointestinal bleeding 1.02 1.51 (1.50,
1.191.89;
P
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Patients taking the NOACs may present with an acute coronary
syndrome (ACS) and/or undergo percutaneous coronary interven-
tion (PCI). Concomitant use of antiplatelet therapy with the
NOACs significantly increases bleeding risk,
96
as is the case withcombining any OAC with antiplatelet therapy. In AF patients at
risk of stroke, and irrespective of HAS-BLED score, OAC still
confers benefit (reduced mortality and major adverse cardiac
events) but with more bleeds.97 In the absence of robust data, in
AF patients with an ACS or PCI/stenting, recommendations
based on expert consensus on the management of such patients
should be followed, as found within the 2010 ESC Guidelines or
current European or North American consensus documents.98100
Thus, a period of triple therapy is needed (OAC plus aspirin plus
clopidogrel), followed by the combination OAC plus single antipla-
telet drug and, after one year, management can be with OAC
alone in stable patients, where OAC can be adjusted-dose VKA
therapy or probably a NOAC. Notably, the only trial where clopido-
grel use was not contraindicated was RE-LY, so the data on triple
therapy with a NOAC (when given at stroke prevention doses in
AF patients) are limited.
A patient taking dabigatran may present with an ACS and, given
the non-significant but small numerical increase in MI events with
dabigatran compared with warfarin,71,72 the concerned clinician
may consider the use of a VKA or an alternative NOAC (e.g. riv-
aroxaban or apixaban). There is little evidence to support this, asthe relative effects of dabigatran vs.warfarin on myocardial ischae-
mic events were consistent in patients with or without a baseline
history of MI or coronary artery disease. Although twice-daily
low-dose rivaroxaban (2.5 mg or 5 mg b.i.d.) has been used with
some benefit in ACS,101 there are no data on ACS relating to
the dose of rivaroxaban used for anticoagulation in AF (20 mg
o.d.). Apixaban, used in the stroke prevention dose (5 mg b.i.d.)
in the ACS setting in combination with aspirin plus clopidogrel,
was associated with no reduction in cardiovascular events but an
excess of major bleeding.102 Patients with AF and stable vascular
disease (i.e. no acute events or revascularization for .12
months, whether coronary or peripheral artery disease) can be
Antiplatelet therapy with aspirin plus clopidogrel, orless effectivelyaspirinonly, should be considered in patients who refuse any OAC, or cannot tolerate
anticoagulants for reasons unrelated to bleeding. If there are contraindications to
OAC or antiplatelet therapy, left atrial appendage occlusion, closure or excision
may be considered.Colour: CHA
2DS
2-VASc; green = 0, blue = 1, red 2.
Line: solid = best option; dashed = alternative option.AF = atrial fibrillation; CHA
2DS
2-VASc = see text; HAS-BLED = see text;
NOAC = novel oral anticoagulant; OAC = oral anticoagulant;
VKA = vitamin K antagonist.aIncludes rheumatic valvular disease and prosthetic valves.
Valvular AFa
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managed with OAC alone, whether as adjusted dose VKA therapy
or, probably, a NOAC. In such stable patients, there is no need for
concomitant aspirin, which could increase the risk of serious haem-
orrhage, including intracranial haemorrhage.
Patients taking the NOACs may also present with an acute is-
chaemic stroke. If the aPTT is prolonged in a patient taking
dabigatran (or the PT with rivaroxaban), it should be assumed
that the patient is anticoagulated, and thrombolysis should not
be administered.103 Given that dabigatran 150 mg b.i.d. did result
in a significant reduction in both ischaemic and haemorrhagic
stroke, should the acute ischaemic stroke occur whilst the
patient is taking rivaroxaban or apixaban (neither of which
Recommendations for prevention of thromboembolism in non-valvular AF
Recommendations Classa Levelb RefC
Antithrombotic therapy to prevent thromboembolism is recommended for all patients with AF, except in those
patients (both male and female) who are at low risk (aged
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significantly reduced ischaemic stroke, compared with warfarin, in
their respective trials), the clinician may consider the use of dabi-
gatran 150 mg b.i.d. instead. Algorithms illustrating the choice of
antithrombotic therapy and the management of bleeding in
patients on NOACs in patients with AF are shown in Figures 1
and2. Although NOACs may be preferred on the basis of clinical
trial data clinicians should remain aware that clinical experience
with these agents is still limited and that care, vigilance and
further information on their effectiveness in clinical practice are
needed.
Key points
The efficacy of stroke prevention with aspirin is weak, with apotential for harm, since the risk of major bleeding (and ICH)
with aspirin is not significantly different to that of OAC,
especially in the elderly.
The use of antiplatelet therapy (as aspirinclopidogrel combin-
ation therapy orless effectivelyaspirin monotherapy for
those who cannot tolerate aspirin clopidogrel combination
therapy) for stroke prevention in AF should be limited to the
few patients who refuse any form of OAC.
The CHA2DS2-VASc score is better at identifying truly low-risk
patients with AF and is as good asand possibly better than
scores such as CHADS2 in identifying patients who develop
stroke and thromboembolism.
The HAS-BLED score allows clinicians to make an informed as-
sessment of bleeding risk and, importantly, makes them think of
the correctable risk factors for bleeding. In patients with a
HAS-BLED score 3, caution and regular review are recom-
mended, as well as efforts to correct the potentially reversible
risk factors for bleeding. A high HAS-BLED score per se
should not be used to exclude patients from OAC therapy.
The NOACs offer better efficacy, safety, and convenience com-
pared with OAC with VKAs. Thus, where an OAC is recom-
mended, one of the NOACseither a direct thrombin
inhibitor (dabigatran) or an oral factor Xa inhibitor (e.g. rivarox-
aban, apixaban)should be considered instead of adjusted-dose
VKA (INR 23) for most patients with AF.
There is insufficient evidence to recommend one NOAC overanother, although some patient characteristics, drug compliance
and tolerability, and cost may be important considerations in the
choice of agent.
5. Left atrial appendage closure
5.1 Rationale and techniques for leftatrial appendage closureThe left atrial appendage (LAA) is considered the main (but not
the only) site of thrombus formation inducing ischaemic stroke
Recommendations for prevention of thromboembolism in non-valvular AF ( Continued)
Recommendations Classa Levelb RefC
Assessment of the risk of bleeding is recommended when prescribing antithrombotic therapy (whether with VKA,
NOAC, aspirin/clopidogrel, or aspirin).I A
25, 54, 59,
60
The HAS-BLED score should be considered as a calculation to assess bleeding risk, whereby a score 3 indicates highrisk and some caution and regular review is needed, following the initia tion of antithrombotic therapy, whether with
OAC or antiplatelet therapy (LoE = A).
Correctable risk factors for bleeding [e.g. uncontrolled blood pressure, labile INRs if the patient was on a VKA,
concomitant drugs (aspirin, NSAIDs, etc.), alcohol, etc.] should be addressed (LoE = B).
Use of the HAS-BLED score should be used to identify modifiable bleeding risks that need to be addressed, but should
not be used on its own to exclude patients from OAC therapy (LoE = B).
IIa A B 25, 54, 60
The risk of major bleeding with ant iplatelet therapy (with aspirinclopidogrel combination therapy and especially in
the elderly also with aspirin monotherapy) should be considered as being similar to OAC.IIa B
18, 21, 23,
24, 26, 35
Recommendations for prevention of thromboembolism in non-valvular AFperi-cardioversion
Recommendations for prevention of thromboembolism in non-valvular AFbleeding
For patients with AF of 48 h duration, or when the duration of AF is unknown, OAC therapy (e.g. VKA with INR 2-3
or dabigatran) is recommended for 3 weeks prior to and for 4 weeks after cardioversion, regardless of the method
(electrical or oral/i.v. pharmacological).
I B 93
In patients with risk factors for stroke or AF recurrence, OAC therapy, whether with dose-adjusted VKA (INR2-3) or a NOAC, should be continued lifelong i rrespective of the apparent maintenance of sinus rhythm following
cardioversion.
I B 110
AF atrial fibrillation; b.i.d. bis in die (twice daily); CHA2DS2-VASc congestive heart failure, hypertension, age 75 (doubled), diabetes, stroke (doubled), vascular disease,
age 6574, sex category (female); CrCl creatinine clearance; HAS-BLED hypertension, abnormal renal/liver function (1 point each), stroke, bleeding tendency or
predisposition, labile INR if on warfarin, elderly (e.g., age .65), drugs (aspirin, NSAIDs, etc.)/alcohol concomitantly (1 point each); INR international normalized ratio;
i.v. intravenous; OAC oral anticoagulant; NOAC novel oral anticoagulant; NSAID non-steroidal anti-inflammatory drug; VKA vitamin K antagonist.aClass of recommendation.bLevel of evidence.cReferences.dApixaban (pending approval EMA and FDA approval): prescribing information is awaited.
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in patients suffering from AF. Trans-oesophageal echocardiography
detects most thrombi in the LAA and low stroke rates are
reported in patients in whom the LAA has been surgically
removed (although these patients were also reverted to sinus
rhythm by various surgical techniques).111,112 Indeed, surgical exci-
sion or stapling of the LAA is widely performed as a concomitant
procedure during open heart surgery. More recently, minimally in-
vasive epicardial techniques and interventional trans-septal techni-ques have been developed for occlusion of the LAA orifice to
reduce the stroke risk.113115 These devices/procedures may
provide an alternative to OAC for AF patients at high risk for
stroke but with contraindications for chronic OAC and, if the effi-
ciency of LAA closure can be conclusively shown, to potentially
replace long-term OAC.
5.2 Results of left atrial appendageclosureAlthough clinically applied for decades, there is no conclusive evi-
dence that surgical LAA excision or occlusion reduces stroke risk
in AF patients, due to a lack of large, controlled trials with system-
atic follow-up.113 Furthermore, there are data to suggest that not
all strokes in AF patients are cardio-embolic or due to AF, and the
LAA is probably not the only left atrial region where thrombi can
potentially originate. This suggests that there may be a need for
antithrombotic therapy in AF patients, even after removal or
closure of the LAA.116
Data from retrospective or observational studies in different
patient populations have shown inconsistent results of surgical
LAA excision or occlusion.117 In addition, no conclusive data are
available on the best surgical technique for performing LAA
closure. Risks of surgical LAA excision include major bleeding
and incomplete LAA occlusion with residual stroke risk.117
Non-randomized observational studies, involving relatively small
numbers of patients, have shown the feasibility of percutaneous
LAA occlusion. Currently, two self-expanding devices, the WATCH-
MAN (Boston Scientific, Natick, MA, USA) and the Amplatzer
Cardiac Plug (St. Jude Medical, St Paul, MN, USA), that are trans-
septally placed in the LAA, are available for clinical use in Europe,
while their evaluation in controlled trials is still in process.
The WATCHMAN LAA system for embolic PROTECTion in
patients with Atrial Fibrillation (PROTECT AF) trial randomized
707 eligible patients either to percutaneous closure of the LAA,
using the WATCHMAN device, or to OAC (INR range 2 3;
control;n
244).115
Patients randomized to LAA occlusion weretreated with OAC for 45 days after the procedure, followed by
dual platelet inhibition for six months and aspirin alone as chronic
therapy. The primary efficacy event rate (composite endpoint of
stroke, cardiovascular death, and systemic embolism) in the LAA
occlusion group was non-inferior to patients treated with OAC.
There was a high rate of adverse events in the intervention group,
mainly due to peri-procedural complications. Many of the adverse
eventsin theintervention group occurred early in thetrial, indicative
of an operator learning curve. The Continued Access to PROTECT
AF (CAP) registry is following patient outcomes beyond the end of
enrolment and demonstrates a learning curve effect with
reduced complication rates after the end of the trial.118 A second
randomized trial, PREVAIL (Prospective Randomized EVAluation
of the Watchman LAA closure device In patients with atrial fibrilla-
tion vs. Long-term warfarin therapy), is currently enrolling patients.
In a feasibility and safety study, LAA occlusion with the Amplat-
zer Cardiac Plug was attempted in 137 of 143 patients, and was
successfully performed in 132 (96%).114 Serious complications oc-
curred in 10 (7.0%) patients. A randomized prospective study with
the device is currently under way (Amplatzer Cardiac Plug Trial).Although the concept of LAA closure seems reasonable, the evi-
dence of efficacy and safety is currently insufficient to recommend
these approaches for any patients other than those in whom long-
term OAC is contraindicated. However, in the absence of con-
trolled clinical data this recommendation is based on expert con-
sensus only. Additional, adequately powered, randomized studies
in patients with high stroke risk and long-term follow-up, compar-
ing interventional/percutaneous/surgical LAA closure with OAC
therapy including NOAC drugs, are needed for adequate assess-
ment of such techniques. The need for lifelong aspirin treatment
after placement of LAA closure devices, and the significant bleed-
ing risk with aspirin,2 may weigh against preference for interven-
tional LAA occlusion. At present, interventional LAA closure is
not indicated simply as an alternative to OAC therapy to reduce
stroke risk.
Key point
Interventional percutaneous occlusion/closure of the LAA has arole in patients with thromboembolic risk who cannot be
managed in the long-term using any form of OAC.
6. Cardioversion withpharmacological agents
Since the publication of the 2010 ESC Guidelines, a new intraven-
ous antiarrhythmic agent, vernakalant, has been approved for
pharmacological cardioversion of AF of 7 days, or 3 days for
patients after cardiac surgery. This update only includes recom-
mendations that have been modified since 2010.
Recommendations for LAA closure/occlusion/excision
Recommendations Classa Levelb RefC
Interventional, percutaneousLAA closure may beconsidered in patients
with a high stroke risk andcontraindications for long-
term oral anticoagulation.
IIb B 115, 118
Surgical excision of the LAAmay be considered in patientsundergoing open heartsurgery.
IIb C
LAA left atrial appendage.aClass of recommendation.bLevel of evidence.cReferences.
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Vernakalant acts preferentially in the atria by blocking several ion
channels, resulting in prolongation of atrial refractoriness and rate-
dependent slowing of atrial conduction, but has little impact on cur-
rents involved in ventricular repolarisation. Vernakalant has a rapid
onset of action and a mean elimination half-life of 35 hours.
6.1 Clinical evidence for vernakalantThe efficacy of vernakalant was investigated in one dose-finding
study, three medium-sized randomized placebo-controlled phase
III clinical studies, one randomized clinical trial with amiodarone as
an active comparator, and a phase IV open-label study
(Table5).119124 In phase III and IV studies, vernakalant was adminis-
tered as a 10-min infusion of 3 mg/kg and, if AF persisted after
15 minutes, a second infusion of 2 mg/kg was given.Patientsenrolled
in the vernakalant studies were primarily men (68%), with a
mean age of 63 years, with approximately half of the patients over
65 years.
In the Atrial arrhythmia Conversion Trials (ACT), vernakalantwas
significantly more effective than placebo in converting AF of7 days
(51.7% and 51.2% compared with 4% and 3.6%, respectively).120,121
Themedian time to conversion was 8 11 minutes, with themajority
of patients (75 82%) converting after the first dose.125
In direct comparison, vernakalant was significantly superior to
intravenous amiodarone in restoration of sinus rhythm within
90 min (51.7% vs. 5.2%; P , 0.0001) and within4 hours afterinfusion
(54.4% vs. 22.6%; P , 0.0001).124 Meta-analysisof the efficacy of ver-
nakalant showed that patients were 8.4 times more likely to convert
to sinus rhythm within 90 minutes after vernakalant infusion, than on
placebo or amiodarone (95% CI 4.416.3), without excess risk of
serious adverse events (risk ratio 0.91; 95% CI 0.61.36).126 In
another meta-analysis vernakalant compared favourably with olderantiarrhythmic agents for rapid cardioversion (within 2 hours).127
Vernakalant retained its efficacy in subgroups of patients with
associated cardiovascular pathologies such as ischaemic heart
disease and hypertension. Specifically, in 274 patients with ischaemic
heart disease (41% with previous MI) included in all studies, the
placebo-subtracted efficacy of vernakalant was 45.7%, compared
with 47.3% in those without ischaemic heart disease, with no
excess in adverse events such as hypotension, bradycardia, and ven-
tricular arrhythmias.128 However, there was a trend towards a
reduced benefit in patients with heart failure.125 Over 95% of
patients who converted to sinus rhythm after receiving vernakalant
injection remained in sinus rhythm at 24 hours. In the pooled ACTI and -III trials, 76% of patients in thevernakalant group received con-
comitant rate-controltreatment withbeta-blockers, calcium antago-
nists or digoxin, and 24% were receiving antiarrhythmic drug
therapy. There was no difference in adverse events.
Vernakalant cardioverted 47% of patients enrolled in ACT II with
postoperative AF after cardiac surgery, compared with 14% who
converted spontaneously on placebo, with a mediantime to conver-
sion of 12 min.122 Vernakalant was ineffective in converting AF of
more than 7 days duration or typical atrial flutter.121,123,129 Conver-
sion of AF to atrial flutter was observed in 8.612.7% of patients
treated with vernakalant, one-third of whom subsequently con-
verted to sinus rhythm.120,121
6.2 Safety of vernakalantThe most common side effects of vernakalant were taste altera-
tions (30%), sneezing (16%), paraesthesiae (10%), and nausea
(9%), which usually resolved within 5 15 minutes.125 Serious
adverse events were reported at similar rates for vernakalant
and placebo (4.1% vs. 3.9%). Transient hypotension occurred in
about 57% of patients treated with vernakalant, with the blood
pressure returning to baseline after approximately 1520
minutes. Hypotension within the first 2 hours was most
common in patients with heart failure (16.1%), leading to discon-
tinuation of treatment in 2.9%.130 Bradycardia was more
common with vernakalant than placebo but seldom led to drug dis-
continuation (0.5%). There was no excess in ventricular arrhythmia
events compared with placebo (5.3% vs.6.3% at 2 hours and 12.5%
vs. 16.5% at 24 hours after the start of treatment) and no
drug-related torsades de pointes120,121,125 However, in patients
with heart failure, non-sustained ventricular arrhythmias (usually
ventricular triplets and salvos) occurred more often on treatment
(7.3% vs. 1.6% on placebo). The QTc interval was typically pro-
longed by 2025 ms and the QRS complex was increased byabout 8 ms after infusion of vernakalant.
The drug is contraindicated in patients with hypotension (systolic
blood pressure ,100 mmHg), ACS within 30 days, NYHA class III
and IV heart failure, severe aortic stenosis, and QT interval prolonga-
tion (uncorrected QT .440 ms), and should be used with caution in
Recommendations for pharmacological cardioversion
of recent-onset AF
Recommendations Classa Levelb RefC
When pharmacological
cardioversion is preferredand there is no or minimalstructural heart disease,intravenous flecainide,propafenone, ibutilide, orvernakalant are recommended.
I A
120, 121,123, 124,126, 127,
131134
In patients with AF 7 daysand moderate structural
heart disease [but withouthypotension
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Table 5 Summary of clinical studies of vernakalant in AF/flutter
Study Design Number of
patients
Underlying heart
disease
AF duration Time to
conversion
(median),
minutes
Conversion
to sinus
rhythm vs.
placebo
or control
(primary
endpointa)
Other efficacy
outcomes
CRAFT119 Double-blind,
dose-ranging,
placebo-controlled,phase II
56
Vernakalant 2 + 3 mg/
kg: n= 18;Vernakalant 0.5 + 1
mg/kg: n= 18
Placebo: n= 20
Hypertension, 57%;
diabetes, 23%
AF 372 h
(mean, 11.519.5 h)
14 61% (vernakalant
2 + 3 mg) vs. 5%,
P
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patients with NYHA I or II heart failure because of increased risk of
hypotension. At present, vernakalant should be avoided in patientswith reduced LVEF (35%) because of limited experience.
The integration of vernakalant into the general schema for
pharmacological and electrical cardioversion is shown in Figure3 .
Key Points
Vernakalant is effective in cardioversion of patients with AF 7
days or AF 3 days after cardiac surgery and provides a rapid
antiarrhythmic effect with approximately 50% of patients con-
verting within 90 minutes after the start of treatment and a
median time to conversion of 814 minutes.
Vernakalant is administered as a 10-minute infusion of 3 mg/kgand, if AF persists after 15 minutes, a second infusion of 2 mg/
kg can be given.
Vernakalant has a satisfactory safety profile in patients with
minimal-to-moderate heart disease, including ischaemic heart
disease, but should be used with caution in haemodynamically
stable patients with NYHA class I and II heart failure, because
of increased risk of hypotension and non-sustained ventricular
arrhythmias in these patients.
Vernakalant is contraindicated in patients with hypotension
,100 mmHg, recent (,30 days) acute coronary syndrome,
NYHA class III and IV heart failure, severe aortic stenosis, and
QT interval prolongation (uncorrected QT .440 ms).
7. Oral antiarrhythmic drugtherapy
7.1 Upstream therapyIn the last several years, a number of trials investigating upstream
therapy for prevention of AF have been reported.135,136 All of
the recent placebo-controlled, double-blind trials with angiotensin-
receptor blockers (ARBs) and the majority of trials with polyunsat-
urated fatty acids failed to show convincing results.136140 There is
now very little reason to consider the use of such therapy for the
prevention of AF recurrence in patients with little or no underlying
heart disease. It may still be justified to co-prescribe an ARB or an
angiotensin-converting enzyme inhibitor with an antiarrhythmic
drug to increase the likelihood of maintaining sinus rhythm after
cardioversion.136
7.2 Principles of antiarrhythmic drugtherapyOral antiarrhythmic drug therapy can be considered for the treat-
ment of recurrent (paroxysmal and persistent) AF. Several
meta-analyses and systematic reviews have confirmed antiarrhyth-
mic efficacy whilst raising signals of concern related to adverse
events and mortality.141144 For this reason, it is important to em-
phasise that antiarrhythmic drug therapy should only be offered to
control resistant symptoms due to recurrent AF and that a safety-
Haemodynamic instability
Severe None
Patient/physician choice
Structural heart disease
Moderate
Intravenousamiodarone
Electricalcardioversion
Intravenousflecainideibutilide
propafenone
vernakalant
Pill-in-the-pocket(high dose oral)c
flecainidepropafenone
Intravenousibutilidea
vernakalantb
Intravenousamiodarone
Intravenousamiodarone
ElectiveEmergency
Yes No
Electrical
Pharmacological
Recent-onset AF
aIbutilide should not be given when significant left ventricular hypertrophy
(1.4 cm) is present.bVernakalant should not be given in moderate or severe heart failure, aorticstenosis, acute coronary syndrome or hypotension. Caution in mildheart failure.c'Pill-in-the-pocket' technique preliminary assessment in a medically safeenvironment and then used by the patient in the ambulatory setting.
Figure 3 Indications for electrical and pharmacological cardioversion, and choice of antiarrhythmic drugs for pharmacological cardioversion
in patients with recent-onset AF.
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Table 6 Summary of clinical studies of dronedarone in AF
Study Patients
(n)
Patient
characteristics
Dose of
dronedarone
Placebo
controlled
Primary
endpoint
Follow-
up
(months)
Outcome Comments
DAFNE152 199 Post
cardioversion
400 mg b.i.d.
600 mg b.i.d.
800 mg b.i.d.
Yes Time to first
AF recurrence
6 Dronedarone 400 mg b.i.d.
significantly prolonged
median time to first AFrecurrence vs. placebo:
60 vs. 5.3 days (P= 0.026);
RRR 55% (95% CI
2872%;
P= 0.001)
Higher doses were
ineffective and were
associated withdiscontinuation
rates of 7.6% and
22.6%; conversion
rates were 5.8%,
8.2%, and 14.8% vs.
3.1% on placebo
EURIDIS153 615 Paroxysmal
or persistent
AF (post
cardioversion)
400 mg b.i.d. Yes Time to first
AF recurrence
12 Median time to first AF
recurrence was 41 days
on dronedarone vs. 96
days on placebo (P= 0.01)
Ventricular
rates during AF
recurrence were
significantly lower
on dronedarone
ADONIS153 630 Paroxysmal
or persistent
AF (post
cardioversion)
400 mg b.i.d. Yes Time to first
AF recurrence
12 Median time to first AF
recurrence was 59 days
on dronedarone vs. 158
days on placebo (P=
0.002)
Dronedarone
reduced ventricular
rates during AF
recurrence vs.
placebo
ERATO154 630 Permanent AF
with ventricular
rates >80
b.p.m. on
rate-controlling
therapy
400 mg b.i.d. Yes Mean 24-h
ventricular rate
at 2 weeks
6 Ventricular rates were
12 b.p.m. lower on
dronedarone vs. placebo
Peak heart rates
during exercise were
24 b.p.m. lower on
dronedarone vs.
placebo
ANDROMEDA149 67
(1000
planned)
Congestive
heart failure; EF
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first principle should prevail. In this regard, the finding that persist-
ent episodes of AF can be reduced or delayed by short-term
(4 weeks post cardioversion) antiarrhythmic therapy may allow
shorter treatment durations.
Antiarrhythmic drug therapy for AF has generally been given as
long-term therapy. A recently published trial, the Flec-SL (Flecai-
nide Short Long) trial145 randomized 635 patients (mean age
64 years, 64% male, 97% preserved left ventricular ejectionfraction, 6% coronary artery disease, mean left atrial diameter
47 mm) to (i) no antiarrhythmic drug therapy (81 patients), (ii)
long-term therapy (263 patients), or (iii) to short-term antiarrhyth-
mic drug therapy limited to four weeks after cardioversion
(261 patients). The trial tested the hypothesis that short-term
therapy was non-inferior to long-term therapy. Patients were fol-
lowed for six months by daily telemetric ECG recording for the
primary outcome of persistent AF or death. The trial demon-
strated that short-term therapy conveyed a slightly inferiorbut
still effectiveantiarrhythmic action, estimated at 80% of the
effect of long-term therapy six months after cardioversion. One
prior trial compared episodic amiodarone treatment to continuous
treatment, assessing a composite primary outcome containing effi-
cacy and safety events. In that trial, episodic amiodarone was not
nearly as effective as continuous amiodarone.146 Based on that
trial and on the pharmacokinetics of amiodarone, especially its
long half-life, amiodarone does not seem to be suitable for short-
term antiarrhythmic drug therapy.147 Taken as a whole, the avail-
able information suggests that short-term antiarrhythmic drug
therapy after cardioversion should not be the default type of treat-
ment and should not be considered with amiodarone, but may be
useful in patients who are either at high risk for drug-induced
adverse effects or for patients with infrequent recurrences of AF.
7.3 Update on dronedaroneDronedarone is a benzofuran derivative, structurally related to
amiodarone, which has recently been approved for the treatment
of paroxysmal or persistent AF. Dronedarone is a multichannel
blocker that inhibits sodium and potassium channels, shows a non-
competitive antiadrenergic activity, and has calcium antagonist prop-
erties. The drug is more effective in maintaining sinus rhythm than
placebo but inferior to amiodarone in that respect (Table6). In the
ATHENA (A placebo-controlled, double-blind, parallel arm Trial
to assess the efficacyof dronedarone 400 mg b.i.d. for the prevention
of cardiovascular Hospitalization or death fromany cause in patiENts
with Atrial fibrillation/atrial flutter),148 a large outcome trial in
patients at moderate risk for cardiovascular events, who had parox-ysmal or persistent AF,dronedarone wasassociated witha significant
reduction in cardiovascular outcome events, including the compos-
ite of unplanned cardiovascular hospitalizations and all-cause
morta